The overall goal of this program project grant is to define the role that HIV infected macrophages play in the pathogenesis of advanced HIV disease, and the long lived HIV infected macrophage reservoir by studying simian models and subsequently humans with HIV associated dementia (HAD). Preliminary studies with a novel class of drugs (polyamine biosynthesis inhibitors, PBI) in vitro showed selective killing of HIV DNA containing blood macrophages from patients with HAD and advanced HIV disease. Initial studies with a PBI in a rhesus monkey simian immunodeficiency virus (SIV) encephalitis induction model showed selective loss of SIV containing blood and brain tissue macrophages in vivo after three injections of drug. The proposed studies will be coordinated by Michael McGrath M.D., PhD. at UCSF who has a long history of evaluating the role of MOs in the pathogenesis of HIV disease and in macrophage targeted drug development. This program project will incorporate centers of excellence for studying SIV disease in vivo (Ken Williams, Harvard), clinical evaluation of anti-HIV and dementia drugs in vivo (Valcour, Shikuma, Shiramizu, U of Hawaii), and the development of novel diagnostic and therapeutic approaches to the HIV DNA reservoir and macrophage associated diseases (Ken Hadlock, Pathologica LLC, Burlingame CA.) This program fulfills requirements of the RFA-AI-06-009 announcement in that it incorporates both academic and corporate research programs aimed at developing novel HIV therapies, integrating both preclinical and clinical programs in animal and human systems. Three projects, one at each center and 3 cores are proposed for the program project grant. Specific components of this program include: Project 1) PL: Ken Hadlock, Pathologica LLC. Mechanism of polyamine biosynthesis inhibitors (PBI) in killing/regulation of HIV infected macrophages, Project 2) PL: Ken Williams, Harvard. Studies of PBI activities in simian models of HAD, Project 3) Preclinical and clinical studies of HIV DNA reservoir in patients with advanced HIV disease and HAD, Administrative Core A) Director Michael McGrath, UCSF. This core provides the oversight and coordination of all of the studies defined in the three projects and two other cores, Assay Core B) Director: Ken Hadlock, Pathologica, LLC. This core program provides quantitative molecular assay support for all three projects. PBI drug manufacture Core C) Director: Ken Hadlock, Pathologica, LLC. This core provides drug for use in all three projects, from the preclinical studies in Projects 1 and 3 to the clinical studies in animals (project 2) and humans (project 3).